ABSTRACT Bone marrow failure syndromes (BMFS) include myelodysplastic syndrome (MDS), aplastic anemia (AA) and paroxysmal nocturnal hemoglobiuria (PNH) and are diseases characterized by failed blood production, stem cell failure and various degrees of clonality marked by the presence of somatic genomic lesions. These conditions have not only a growing socioeconomic and medical importance, but also their basic study has provided ground-breaking discoveries with implications for the understanding the physiologic pathophysiologic mechanisms within hematopoiesis and beyond for the whole field of hematology. The main focus of my early scientific career as physician scientist and hematologist has been on study immune pathogenesis, ways of stem cell enumeration, mechanisms of stem cell damage and molecular genetics of BMFS. The latter themes initially included discovery of new somatic and germ line lesions and subsequently transitioned to mechanistic studies. These lines of investigations, specifically pertinent in this R35, yielded important clues as to the mutational spectrum in MDS and later led to the growing appreciation of the role of clonal hierarchy and dynamics not only in MDS, but also in AA and PNH. Our team has made significant contribution to these advances made possible by a continuous funding from NHLBI and other sources. Our experience, commitment to the field, and created infrastructure provide a solid base for proposed expansions of ongoing molecular studies towards new paradigm-shifting scientific goals. By taking advantage of the newest molecular discoveries of somatic and germ line mutations and through progress in clarifying their mechanistic consequences, we believe that it is now time to advance translational goals to make tangible advances in medical care including diagnostics and therapeutics for BMFS. Such investigations would also contribute to improved understanding of basic disease mechanisms mediated by selected subset of common and important somatic mutations. We will use the newest technologies, including single cell sorting and sequencing, to further study the clonal architecture to identify targetable early events and also determine the dependence of clonal cells on these events following acquisition of subclonal lesions. These genomic investigations will involve also germ line lesions and their contribution of late manifestation of adult BMFs. They will provide substrates for mechanistic studies aiming at development of conceptually new therapeutic strategies. This theme will initially involve TET2 and other dioxygenases, DNMT3A and other histone and DNA methylases and spliceosomal mutations. These studies will also define the impact of germ line alteration and using integrative approaches identify disease subgroups by the presence of convergent pathways and results will provide a canvas for the rational selection of most suitable targets for development of new treatment strategies.